The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. T follicular helper (Tfh) cells are CD4+ T cells specialized in providing help to B cells, particularly within germinal centers (GCs). With Tfh cells delivering help signals via costimulatory molecules and cytokines, B cells undergo somatic hypermutation and affinity maturation within GCs, generating plasma cells and memory B cells and with greater protective efficacy. Tfh cells are also found in great abundance in peripheral blood of patients with systemic lupus erythematosus and myasthenia gravis, suggesting a role of Tfh cells in pathogenic autoantibody production. Therefore, increasing our knowledge of Tfh cell development and function in normal and aberrant immune responses will aid design of more efficacious vaccines against infectious diseases and discovery of novel therapeutic approaches to treat autoimmunity. Tcf1 and Lef1 transcription factors are essential for normal T cell development and are known to interact with the ?-catenin coactivator for gene regulation. Previously we showed Tcf1 and Lef1 critically regulate longevity and maturation of memory CD8+ T cells. We conditionally ablated both genes in mature T cells to bypass the impact on thymocyte development, and showed Tcf1 and Lef1 are also essential for Tfh differentiation. Our recent ChIPseq mapping of the Tcf1 cistrome in Tfh cells revealed it is broadly associated with the Tfh genetic program, beyond the reported Bcl6-Blimp1 axis. We also made a surprising finding that Tcf1 and Lef1 are not only transcriptional regulators but also have intrinsic histone deacetylase (HDAC) activity. These unexpected findings led us to hypothesize that Tcf1 and Lef1 couple the intrinsic HDAC activity with their ?-catenin- and DNA-binding capacity to shape the enhancer landscape, transcriptional programs, and functionality of Tfh cells. Our specific aims are: Specific Aim 1. To determine how Tcf1 and Lef1 control enhancer organization and transcriptional programming during effector Tfh differentiation.. Specific Aim 2. To investigate the necessity and sufficiency of ?-catenin pathway in Tfh differentiation. This application will use viral infection models to systematically investigate Tcf1/Lef1 transcription factors, ?-catenin coactivator, and their interaction as novel regulators of Tfh differentiation at the initiation, effector and memory phases. It is particularly exciting that Tcf1 and Lef1 directly bridge transcriptional and epigenetic regulation in Tfh cells, which will establish a new paradigm in coordination of genetic and epigenetic regulation. These studies will thus provide rationales for utilizing the Tcf1/Lef1-?-catenin pathway to enhance Tfh functions for more effective vaccines or to dampen Tfh activities for treating autoimmune diseases.